Potassium Phosphate, Tribasic → 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide

HRID 73744Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 73744
[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[C:11](N2CC[C@H](O)C2)=[N:12][CH:13]=[C:14]([CH:29]=1)[C:15]([NH:17]C1C=CC(OC(Cl)(F)F)=CC=1)=[O:16].[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[N:42]1[C:46](B2OC(C)(C)C(C)(C)O2)=[CH:45][CH:44]=[N:43]1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[N:42]1[C:46]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:29]=2)[C:15]([NH2:17])=[O:16])=[CH:45][CH:44]=[N:43]1

Komponenten

7

Edukt 3

HCID 62657Potassium Phosphate, TribasicHCID 115872081-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 86702602(S)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

Produkt 1

HCID 1317318385-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 1140TolueneLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

K3PO4 (41.3 mg, 0.195 mmol) was added to a solution of (S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 8.1, 30 mg, 0.067 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (36.2 mg, 0.13 mmol) in toluene (0.32 mL) in a vial which was flushed with argon. Pd(PPh3)4 (3.75 mg, 0.032 mmol) was added. The vial was sealed and heated at 110° C. for 18 h. After cooling at RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH) to afford N-(4-(chlorodifluoromethoxy)phenyl)-6-(S)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide, a portion of which (21 mg, 0.039 mmol) was dissolved in DCM (0.5 mL), treated with TFA (0.141 mL, 1.82 mmol) and stirred at RT for 3 h. The RM was poured into 10% aq. Na2CO3 (10 mL) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH) to afford the title compound. HPLC (Condition 4) tR=4.49 min, HPLC Chiral (CHIRALCEL® OD-H, 250×4.6 mm, eluent:n-heptane/EtOH/MeOH (85:10:5), 1 mL/min, UV DAD, tR=13.32 min, UPLC-MS (Condition 3) tR=0.92 min, m/z=450.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.76 (m, 1H) 1.77-1.92 (m, 1H) 2.86-2.97 (m, 1H) 3.18-3.35 (m, 2H) 3.34-3.47 (m, 1H) 4.10-4.24 (m, 1H) 4.66-4.93 (m, 1H) 6.28-6.42 (m, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.85 (d, J=8.99 Hz, 3H) 7.96-8.05 (m, 1H) 8.64-8.81 (m, 1H) 10.17 (s, 1H) 12.80-13.14 (m, 1H).

Aufarbeitung

  1. customwas flushed with argon
  2. customThe vial was sealed
  3. temperatureAfter cooling at RT
  4. washwashed with brine
  5. dry with materialdried over Na2SO4
  6. customthe solvent was evaporated off under reduced pressure
  7. customto give a crude product
  8. customwas purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH)

Quellen und Nachweise

ORD-Eintrag
ord-eefcae6a025846d6932e874f8dce3737
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08829195B2

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